The lung hypoplasia associated with congenital diaphragmatic hernia (CDH) is largely responsible for the high mortality of the common congenital malformation. The fact that CDH can be diagnosed in utero at mid-trimester means that improvement prior to birth may be possible if we can determine the molecular etiology or understand the critical pathways responsible for the malformation. We will use previously collected and prospective CDH and normal fetal lungs to study the expression of genes known to be associated with human CDH or mouse knockouts which have CDH phenotypes (Aim II). Similar we will study candidates that arise from Drosophila, chick, or rodent screens, then determine if complementation can correct phenotypes of CDH in these models (Aim II). As the next step we will clone human homologous and design human probes from the coding regions of the most promising candidates for mutational scanning of CDH patients and their families (Aim III). A database will be established for all CDH patients who came to the MGH for prospective care by our Pediatric Surgical Service, and their families, as well as for all of those patients cared for by the Pediatric Surgical Service since 1970 (Aim 1). These patients and families will provide blood and tissue from which cell lines will be immortalized for chromosomal and genetic analysis. Loss of homozygosity scanning will be done for 15q22-ter, 12q, and 8q regions (Aim IV) and candidate genes revealed by the scans will be tested for expression in the discarded fetal normal and CDH lungs and for complementation of CDH phenotype in the animal model. Genes which are abnormal in CDH patients can be complemented in the various small animal models will be used to design treatment strategies for humans with CDH after appropriate testing in larger animal models.
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